Malignant tumors are characterized, besides from the uncontrolled cellular proliferation, by their capacity to invade normal peritumoral tissues. Tumor invasion is a complex process developed according to the following consecutive stages: a) adhesion of the tumor cells to proteins of the extra-cellular matrix; b) degradation of the proteins of the extra-cellular matrix by proteases that create extra-cellular spaces that the tumor cells use to, c) migrate through a dynamic and complex mechanism that requires synthesis of new portions of the cytoplasmic membrane and reorganization of the cytoskeleton (Giese A, Westphal M. Neurosurgery 1996; 39: 235-252). The cells that from the tumor mass invade the normal peritumoral-tissue have their genetic program of cellular death disabled and therefore, the tumor cells that migrate to invade the peritumoral intact tissues, elude the apoptosis (Mariani I et al. Clin Cancer Res 7:2480-2489, 2001). When the grouped tumor cells reach 2 to 3 mm3 volume, the tumor cells synthesize large amounts of angiogenic factors to counteract the hypoxic situation of this primary tumor, (Folkman J. N. Engl J Med 285: 1182-1186, 1971; Carmeliet P, Jain R K. Nature 407: 249-257, 2000; Yancopoulos G D et al. Nature 407: 242-248, 2000) that activate the peritumoral blood vessels so that they form new blood vessels (angiogenesis) that invade the tumor to supply the oxygen and the nutrients and eliminate products from the tumor catabolism. The same cellular processes that occur during the tumor invasion (motility and absence of apoptosis) occur centripetally during tumor angiogenesis. Therefore, the inhibition of the invasive capacity of the tumor cells and of the endothelial cells should produce a delay in tumor growth by inhibiting the tumor expansion, reducing angiogenesis and promoting apoptosis. Therefore, an effective treatment against cancer should inhibit the migration, the angiogenesis and increase apoptosis without producing these effects in normal cells.
There are numerous anti-tumor and antiangiogenic agents at various stages of clinical development in oncology (Brem S. Cancer Control 6: 436-458, 1999), of which a significant number are polypeptides that the body uses to counteract the effect of the positive regulators of angiogenesis (Hagerdom M, Bikfalvi A. Crit. Rev One Hemat 34: 89-110, 2000). However, when said polypeptides are compared with compounds with a significantly lower molecular weight, their pharmacological inconveniences become evident. On the other hand, it has been proven that different synthetic compounds containing aromatic rings in their molecular structure and acting as inhibitors of the mitogenic activity induced by growth factors are cytotoxic for quiescent or non tumor cells (Lozano R M J Mol Biol 281: 899-9115, 1998). Therefore, there is still need to find compounds with anti-tumor, antiangiogenic and proapoptotic activity with low toxicity for healthy, quiescent, non tumor cells. There is presently a great interest for the search of new therapeutic indications for old medicines. In this connection, it has been recently proven that different antibiotics, besides from their antimicrobial activity, have antiproliferative effects, such in the case of rapamycin (Morice M C et al. N Engl J Med 346: 1773-1780, 2002), or of the neomycin (Cuevas P. et al. Neurol Res 224: 389-391, 2002); or are useful as anxiolytics such as norfloxacin (fluoroquinolone) (Johnstone T B et al. Nat Med 10; 31-32, 2004).
Psoriasis is an angiodependent chronic disease that affects 2-3% of the world population and is characterized by epidermic hyperplasia, dermo-epidermic infiltration of inflammatory cells and T lymphocytes, and a very evident development of vascularization (Robert C, Kupper T. S. New Engl. J. Med, 1999; 341:1817-1828), together with a reduction of the cell death due to apoptosis (Kocak M et al. Int J Dermatol 42: 789-793, 2003). Presently, there is no curative treatment for psoriasis. The antipsoriatic treatment may be topical or systemic, depending on the extension and severity of the disease. The mostly used anti psoriatic topical therapy consists of different types of corticoids, but the extended use of these compounds is associated with skin atrophy, stretch marks and telangiectasia (Baker B S, Fry L. Cutis 1999; 64: 315-318). The systemic therapy with immunosuppressant medicines is associated to very severe side effects (Wolina V. et al. Clin Rheumatol 2001: 20: 406-410). For example, the use of cyclosporine for treatment of psoriasis may produce nephrotoxicity (interstitial fibrosis and tubular atrophy), hypertension, hypomagnesaemia, hypercalcemia and hepatic dysfunction (Travis L, Weinberg J M. Drugs of Today 2002; 38: 847-865). The standing use of another immunosuppressant medicine for treatment of psoriasis, tacrolimus, may produce hypertension, nephrotoxicity and immunosuppression (Jegasothy B V et al. Arch Dermatol 1992; 128: 781-785). It has been recently described that the topic application of the tacrolimus immunosuppressant accelerates carcinogenesis in mouse skin (Niwa Y, Terashima T, Sumi H. B J Dermatol 2003; 149: 960-967). Therefore, there is need for new antipsoriatic compounds proving to be efficient without producing evident side effects such as those associated with the most common anti-psoriatic treatments.
The 2,5-dihydroxybenzenesulfonic acid is a derivative of the 2,5-dihydroxybenzoic acid, pharmacologically prescribed in the form of different salts (mainly calcium, potassium, and magnesium), which provides stability. The 2,5-dihydroxybenzenesulfonic acid has been used since the 70's as an oral vasculotropic medicine (Berthet P et al Int J. Clin Pract 53: 631-636, 1999).
The 2,5-dihydroxybenzenesulfonic acid inhibits platelet aggregation, increase of capilar permeability and blood viscosity in patients with diabetic retinopathy (Bayer J. et al. Dtsch. Mod Wschr 1980; 46: 160-1608; Banarroch I. S. et al. Ophthalmic Res 1985; 17; 131-138; Michal M, Giessinger N. Thromb Res 1988; 51: 593-605). The metabolism and the pharmacokinetics of this compound in the human being is known since year 1974 (Benakis A. et al. Thérapie 1974; 29: 211-219). Recent experiments have proven that the 2,5-dihydroxybenzenesulfonic acid increases the activity of the endothelial isoform of the nitric oxide synthase [endothelial nitric oxyde synthase (eNOS)] in rat endothelial cells without producing cytotoxic effects (Suscheck C. et al. Bt J Pharmacol 1997; 122: 1502-1508). In addition, the 2,5-dihydroxybenzenesulfonic acid potentiates the in vitro relaxation of human penile arteries (Angulo J et al. Br J Pharmacol 2003; 139: 854-862). There is experimental evidence that the 2,5-dihydroxybenzenesulfonic acid (formulated as a calcium or magnesium salts) possesses in vitro antioxidant activities (Brunet J et al. Fundam Clin Pharmacol 12: 205-212, 1998).
The present invention is based on the discovery of new activities of the 2,5-dihydroxybenzenesulfonic acid and/or its salts, associated to their antiproliferative, anti migratory, antiangiogenic and proapoptotic capacity in non quiescent cells, activities that combined, justify their employment as a useful compound for treatment of angiodependent diseases such as the case of cancer, characterized by hyperproliferation, cell invasion and excessive angiogenesis, together with a deficit in cell death due to apoptosis, without causing toxicity for non-tumor healthy or quiescent cells. Gliomic tumor cells have been used in experiments because gliomas are very invasive tumors with a significant angiogenic capacity and a significant apoptotic deficit (Merzak A, Pilkington G J. Cancer Metastasis Rev 16: 155-177, 1997).
The present invention is also based on the proven fact that the 2,5-dihydroxybenzenesulfonic acid and/or its salts possess, in a combined form, antipoliferative, antiangiogenic, and proapoptotic effects and therefore its therapeutic efficacy has been evaluated in chronic psoriatic plaques characterized by epidermic hyper-proliferation, acute dermal angiogenesis and apoptotic deficit (Karasek M A, Cutis 64: 319-322, 1999).
This invention relates then to the search of new treatments for cancer and other angiodependent diseases an it is based on the fact that the 2,5-dihydroxybenzene sulfonic acid and/or its salts have proven their capacity to inhibit growth and migration and induce the apoptosis in in vitro tumor cells as well as the capacity to inhibit the in vivo angiogenesis induced by fibroblast growth factor (FGF). Therefore, due to the combination of these abilities, the mentioned compounds become useful for the treatment of malignant tumors and hematological neoplastic diseases as well as for treatment of other severe vascularization related pathologies (angiodependent diseases).